The protection of crops from weeds and other vegetation that inhibits crop growth is a constantly recurring problem in agriculture. To help combat this problem, researchers in the field of synthetic chemistry have produced an extensive variety of chemicals and chemical formulations effective in the control of such unwanted growth. Chemical herbicides of many types have been disclosed in the literature and a large number are in commercial use. Commercial herbicides and some that are still in development are described in The Pesticide Manual, 13th Edition, published 2003 by the British Crop Protection Council.
Many herbicides also damage crop plants. The control of weeds in a growing crop therefore requires the use of so-called ‘selective’ herbicides, which are chosen to kill the weeds while leaving the crop undamaged. In practice, few herbicides are, fully selective, in that they will kill all the weeds and leave the crop untouched at a particular application rate. The use of most selective herbicides is actually a balance between applying enough herbicides to acceptably control most of the weeds and causing only minimal crop damage. One known selective herbicide is mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)cyclohexane-1,3-dione).
It is well known that certain substances can form different crystal structures, or polymorphs. In many cases, only one of the polymorphs is thermodynamically stable. Mesotrione, a broadleaf herbicide, is an example of a substance that can form polymorph crystals. Crystallization of mesotrione is carried out by a pH shift in a predominantly aqueous solution whereby the soluble salt is converted to the insoluble free acid resulting in high yield. It has recently been discovered that mesotrione exists in two polymorphic forms: the thermodynamically stable form, referred to herein as Form 1; and the metastable form, referred to herein as Form 2.
For aqueous crystallization a large difference in size between Form 1 and Form 2 mesotrione was seen and this is a very useful technique for assessing the presence of Form 2. The powder X Ray Diffraction (PXRD) patterns and data for the two polymorphic forms are also distinctly different
In the commercial manufacture of mesotrione it is important to produce the thermodynamically stable polymorph, referred to as Form 1. However, due to the size of the crystals, milling is required to reduce the crystal size when formulating into an agrochemically acceptable composition. Form 2 is already of a size that would be suitable for formulating into an agrochemically acceptable composition, however, Form 2 is thermodynamically unstable and would gradually convert to Form 1; consequently any formulation prepared therefrom can lead to instability problems during storage, or it can result in difficulties during the application of the product in the field.
A further problem exists in that Form 1 is currently the form used in preparing agrochemically acceptable formulations, but during the manufacturing process, Form 2 is readily made when mesotrione is recrystallized in aqueous solution. Due to Form 2 being very fine, it is difficult to harvest the solids and production time is lost while trying to remove it from the system. If the Form 2 material obtained during recrystallization cannot be converted to Form 1, then it must be disposed of, resulting in lost revenue and inefficient production processes.
Commercial manufacture of herbicides is often done in batch reactors. Consequently, the crystallization process, which is typically the last stage of the manufacturing process, is also often conducted in a batch mode. In this mode of operation, a small number of batches yield product that contain the undesirable Form 2 crystals. Formation of Form 2 crystals can be avoided by using solvents during the crystallization. However, the use of solvents will significantly increase the manufacturing costs due to the recovery or disposal of these solvents.
WO 03/099409 teaches the use of solvents to control polymorphism. The use of solvents generates a waste stream which can be difficult to treat because of high solvent loadings, or it requires additional process steps and equipment to recover the solvent from the waste stream.